When injected into the cerebral ventricular or paraventricular nucleus (PVN), Neuropeptide Y (NPY) is the most potent stimulant of food intake known. It also stimulates the release of corticotropin releasing hormone (CRH), ACTH and cortisol. This latter action is dose dependent and shared by the structurally related peptide, pancreatic polypeptide (PP). NPY nerves that influence the PVN arise from the Nucleus Tractus Solitarius in the dorsal vagal comples and the amygdala. Bilateral destruction of the amygdala results in anorexia and weight loss in experimental animals. We propose 1) to compare NPY contents and NPY mRNA levels in that amygdala and PVN of obese and lean rats, 2) examine NPY binding in the hippocampus and PVN of obese and lean rats and mice, 3) examine structure-function requirements fro binding to these regions of the brain, 4) crosslink and characterize these receptor populations in obese and lean animals, 5) contrast NPY's ability to stimulate the release of CRH in obese and lean animals. These studies will be performed in male and female rats. Adrenalectomy abolishes the ability of NPY to stimulate food intake suggesting a relationship between the NPY's ability to stimulate food intake and the HPA axis. Congenital obese rodents, particularly males, exhiit a hyperactive hypothalamic- pituitary-adrenal axis (HPA) and adrenalectomy reverse the obesity in congenitally obese rodents. We will determine the effects of adrenalectomy and steroid supplementation on NPY contents in the amygdala and PVN and NPY binding to the hippocampus and PVN in Sprague Dawley rats. Similar studies will be repeated in obese rats. In prior studies we have established that ob/ob mice fail to release PP in response to a meal, a characteristic thay share with Prader-Willi children. Treatment with bovine PP is the only other treatment, other than adrenalectomy, that reverse the obesity and diabetes seen in these animals . Using autoradiography will have identified novel PP receptor populations in the brain (NTS) and adrenal that may mediate these beneficial effects. We will contrast bbinding of PP to the NTS in bese and lean rats and mice. We will also characterize the PP receptor population in the Zona Fasiculata and determine if PP inhibits corticosterone release. NPY and PP are structurally related peptides that are capable of modifying feeding behaviors and/or the HPA axis. These studies will clarify how these structurally related brain-gut peptides interact to control body weight.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044072-02
Application #
3245552
Study Section
Special Emphasis Panel (SRC (05))
Project Start
1991-06-15
Project End
1995-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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Whitcomb, D C; Puccio, A M; Vigna, S R et al. (1997) Distribution of pancreatic polypeptide receptors in the rat brain. Brain Res 760:137-49
Gettys, T W; Watson, P M; Taylor, I L et al. (1997) RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient beta-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice. Int J Obes Relat Metab Disord 21:865-73
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Okumura, T; Fukagawa, K; Tso, P et al. (1996) Apolipoprotein A-IV acts in the brain to inhibit gastric emptying in the rat. Am J Physiol 270:G49-53
Okumura, T; Taylor, I L; Pappas, T N (1995) Microinjection of TRH analogue into the dorsal vagal complex stimulates pancreatic secretion in rats. Am J Physiol 269:G328-34
Gettys, T W; Rohlfs, E M; Prpic, V et al. (1995) Age-dependent changes in beta-adrenergic receptor subtypes and adenylyl cyclase activation in adipocytes from Fischer 344 rats. Endocrinology 136:2022-32
Okumura, T; Fukagawa, K; Tso, P et al. (1995) Mechanism of action of intracisternal apolipoprotein A-IV in inhibiting gastric acid secretion in rats. Gastroenterology 109:1583-8
Okumura, T; Taylor, I L; Ohning, G et al. (1995) Intracisternal injection of TRH antibody blocks gastric emptying stimulated by 2-deoxy-D-glucose in rats. Brain Res 674:137-41
Okumura, T; Grant, A P; Taylor, I L et al. (1995) Gastric mucosal damage induced by 2-deoxy-D-glucose involves medullary TRH in the rat. Regul Pept 55:311-9

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